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Francis J Giles

Publications and source records attributed to Francis J Giles.

At least 37 records · Page 2Linked to original sources
PubMed2006

Eradication of minimal residual disease in hairy cell leukemia.

Although the nucleoside analogs cladribine and pentostatin produce high response rates in patients with hairy cell leukemia (HCL), a significant number of patients eventually relapse. Several studies have demonstrated that patients with complete remission (CR) have a longer disease-free survival. Therefore, strategies to improve on the initial response to nucleoside analog therapy are likely to be beneficial, at least for a proportion of patients. We have treated 13 patients with newly diagnosed HCL (n = 11) or after failure of one prior chemotherapy (n = 2) with cladribine (5.6 mg/m(2) given intravenously over 2 hours daily for 5 days) followed by 8 weekly doses of rituximab (375 mg/m(2)). All patients achieved a CR and minimal residual disease (MRD) assessed by consensus primer polymerase chain reaction (PCR) or flow cytometry was eradicated in 11 (92%) of 12 and in 12 (92%) of 13 of patients, respectively. There was no decline in the absolute CD4 and CD8 lymphocyte number after rituximab. We conclude that eradication of MRD in HCL is possible. Whether this leads to a reduced risk of relapse would need to be evaluated in a larger number of patients and with longer follow-up. Disease characteristics may potentially be used to identify patients that are more likely to benefit from such additional therapy.

Adult↗
PubMed2006

Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome.

Triapine, an iron chelator and a potent inhibitor of ribonucleotide reductase, has significant anti-leukemia activity. A phase I study of Triapine in combination with ara-C was conducted in 32 patients with refractory acute leukemia and high-risk MDS. Triapine (105 mg/m2/day 6-h infusion) was followed immediately by ara-C [100 (n=4), 200 (n=6), 400 (n=7), or 800 (n=8)mg/m2/day] as an 18-h infusion for 5 consecutive days. Dose-limiting toxicities (DLTs) were observed at the 800 mg/m2 ara-C dose level (one patient each with grade 4 mucositis; grade 4 neutropenic colitis, sepsis; grade 4 neuropathy; and grade 4 hyperbilirubinemia). Therefore, the study was amended to include an ara-C dose level of 600 mg/m2/day, no DLTs occurred in seven patients treated at this dose level. Mean Triapine C(max) and AUC were 1.13 microg/mL and 251.5 minmicrog/mL. Of 31 evaluable patients, 4 (13%) (3 AML, 1 Ph+ALL) achieved a CR (1 at a dose of 800 mg/m2; 2 at 600 mg/m2; 1 at 200mg/m2). The recommended phase II regimen is Triapine 105 mg/m2/day followed by ara-C 600 mg/m2/day for 5 consecutive days every 3-6 weeks.

Acute Disease↗
PubMed2006

Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older.

Outcome of patients with acute myeloid leukemia (AML) who are older than 60 years of age remains unsatisfactory, with low remission rates and poor overall survival. We have previously established the activity of clofarabine plus cytarabine in AML relapse. We have now conducted a phase 2 study of clofarabine plus cytarabine in patients aged 50 years or older with previously untreated AML. Clofarabine was given at 40 mg/m2 as a 1-hour intravenous infusion for 5 days (days 2 to 6) followed 4 hours later by cytarabine at 1 g/m2/d as a 2-hour intravenous infusion for 5 days (days 1 to 5). Of 60 patients, 29 (48%) had secondary AML, 30 (50%) had abnormal karyotypes (monosomy 5 and/or 7 in 15 [25%]), and 11 (21%) showed FLT3 abnormalities. The overall response (OR) rate was 60% (52% CR, 8% CRp). Four patients (7%) died during induction. Adverse events were mainly grade 2 or lower and included diarrhea, nausea, vomiting, mucositis, skin reactions, liver test abnormalities, and infusion-related facial flushing and headaches. Myelosuppression was common. Clofarabine plus cytarabine has activity in adult AML, achieving a good CR rate. However, survival does not appear to be improved compared with other regimens. Modifications of this combination in AML therapy of older patients warrant further evaluation.

Acute Disease↗
PubMed2006

Phase II study of sphingosomal vincristine in patients with recurrent or refractory adult acute lymphocytic leukemia.

BACKGROUND: Outcomes with salvage therapy for patients with recurrent or refractory acute lymphocytic leukemia (ALL) are poor, with complete response (CR) rates reported to be 20-30% and a median survival ranging from 2-6 months. New agents are needed to reduce the recurrence rate after frontline chemotherapy. Vincristine is an important component of ALL therapy. In animal models, the encapsulation of vincristine into sphingomyelin liposomes or "sphingosomes" for injection (SV) has improved efficacy compared with conventional vincristine. METHODS: A Phase II clinical trial of single-agent SV given at a dose of 2.0 mg/m2 every 2 weeks was conducted in patients with recurrent or refractory ALL. Approximately half of the 16 patients who received SV had a first CR duration of less than 1 year, 19% had failed standard induction chemotherapy, and 50% had Philadelphia chromosome-positive disease. SV was the first salvage attempt in 69% of the patients. RESULTS: The overall response rate in the 14 evaluable patients was 14% (1 CR and 1 partial response). Five patients (36%) had transient reductions in bone marrow leukemia infiltrate with subsequent regrowth of the leukemia between SV infusions. Toxicity with limited treatment (median number of doses was two; range, one to five doses) was minimal with expected peripheral neuropathy. CONCLUSIONS: Further study of SV in patients with ALL is warranted. A Phase I-II clinical trial of weekly SV with pulse dexamethasone currently is ongoing.

Adolescent↗
PubMed2006

The role of gemtuzumab ozogamicin in acute leukaemia therapy.

Gemtuzumab ozogamicin (GO) is an immunoconjugate that binds to CD33 on the surface of acute myeloid leukaemia (AML) blasts and, after internalisation, releases a cytotoxic drug, calicheamicin. GO is approved by the US Food and Drug Administration for the treatment of CD33-positive AML at first relapse in patients 60 years and older who are not candidates for other cytotoxic therapy. GO as a single agent has low antileukaemic activity. When given to patients meeting the criteria noted above, it produces a complete response (CR) rate of only 12%, with another 12% achieving CR with inadequate platelet recovery (CRp). The median survival of patients treated with GO monotherapy is 11.2 months. GO therapy at 9 mg/m(2) is complicated with hepatic veno-occlusive disease in 5-10% of patients, particularly prior to or following stem cell transplantation. GO at lower doses combined with chemotherapy as induction or postremission therapy is promising, however, and phase III trials are ongoing. GO is probably most active in acute promyelocytic leukaemia (APL). It is used for induction regimens in high-risk APL and for the elimination of minimal residual APL. Case reports suggest that GO also has activity in CD33-positive acute lymphoblastic leukaemia. In conclusion, single agent GO can induce responses in patients with CD33-positive AML in first recurrence. The future of GO is its use in combination with other cytotoxic agents. Ongoing clinical trials may better define the role of GO combinations, particularly in untreated AML.

Acute Disease↗
PubMed2006

Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies.

Invasive fungal infection remains the most common cause of infectious death in acute leukemia. In this open-label, randomized study, we compared the efficacy and safety of caspofungin with that of intravenous itraconazole for antifungal prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Of 200 patients, 192 were evaluable for efficacy (86 for itraconazole, 106 for caspofungin). Duration of prophylaxis (median, 21 days [range, 1 to 38 days]), demographics, and prognostic factors were similar in both groups. Ninety-nine patients completed antifungal prophylaxis without developing fungal infection (44 [51%] with itraconazole, 55 [52%] with caspofungin). Twelve patients developed documented invasive fungal infections, five in the itraconazole group (four with candidemia and one with Aspergillus pneumonia), and seven in the caspofungin group (two with candidemia, two with disseminated trichosporon species, two with Aspergillus pneumonia, and one with disseminated Fusarium spp). Two patients in the itraconazole group and four in the caspofungin group died of fungal infection (P = 0.57). Grade 3 to 4 adverse event rates were comparable between groups; the most common event in both was reversible hyperbilirubinemia. No evidence of cardiovascular toxicity from intravenous itraconazole was noted among patients older than 60. In conclusion, intravenous itraconazole and caspofungin provided similar protection against invasive fungal infection during induction chemotherapy, and both drugs were well tolerated.

Adolescent↗
PubMed2005

The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

AG-013736 is an oral anti-angiogenesis agent with activity against a variety of receptor tyrosine kinases, including VEGFR-1, VEGFR-2, VEGFR-3, c-kit, and PDGFR-beta. A phase 2 study was conducted in patients with poor prognosis AML or MDS. Twelve patients (six AML; six MDS) were treated with AG-013736 at a dose of 10mg orally daily for a median of 56 days (range, 1-248 days). Median age was 80 years (range, 58-88 years). Grade 3 or 4 drug-related toxicities included hypertension (42%), mucositis (8%) and deep venous thrombosis (8%). No objective responses occurred; two patients with MDS had stable disease for 8.3 and 6.2 months, respectively. Bone marrow expression of VEGFR-1 and VEGFR-2 was observed in 11% and 0% of patients, respectively. Sustained decreases in soluble VEGFR-2 plasma levels with concomitant elevation in plasma VEGF and placental growth factor levels were obtained during the course of therapy with AG-013736. AG-01736 had minimal biologic or clinical activity in this elderly patient population.

Acute Disease↗
PubMed2005

Phase 1 study of ABT-751, a novel microtubule inhibitor, in patients with refractory hematologic malignancies.

PURPOSE: ABT-751 is an oral antimitotic agent that binds to the colchicine site on beta-tubulin. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of ABT-751 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. STUDY DESIGN: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m(2) (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m(2) (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC). RESULTS: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m(2), with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala(185)Thr, was identified in exon 4 of the beta-tubulin gene, TUBB, in three other patients. The recommended phase 2 dose in hematologic malignancies is 175 mg/m(2) daily orally for 21 days every 4 weeks. CONCLUSION: Further assessment of ABT-751, especially in combination with other agents, in patients with acute leukemias is warranted.

AC133 Antigen↗
PubMed2005

Angiogenic factors may have a different prognostic role in adult acute lymphoblastic leukemia.

Angiogenesis plays an important role in solid tumors and hematologic malignancies. The prognostic significance of angiogenic factors in adult acute lymphoblastic leukemia (ALL) remains ambiguous. We therefore analyzed the impact of angiogenic factor levels on overall survival of newly diagnosed adult ALL patients. Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-1 receptor alpha (IL-1Ralpha), IL-6, IL-8, VEGF receptors VEGFR1 and VEGFR2, and thrombopoietin (TPO) were measured in plasma samples of 95 patients by enzyme-linked immunosorbent assay (ELISA). In a univariate Cox proportional hazards model, higher levels of IL-1Ralpha, IL-8, VEGFR1, and VEGFR2 were predictive of poor survival. In contrast, higher levels of VEGF were predictive of longer survival, and higher levels of bFGF suggested a similar trend (P = .09). The multivariate model simultaneously included VEGF (relative risk [RR] for death, 8.01; P = .001 for levels less than or equal to 19.5 pg/mL), IL-1Ralpha (RR, 5.12; P = .007 for levels greater than 373 pg/mL), and VEGFR2 (RR, 4.01; P = .04 for levels greater than 8222 pg/mL) as independent factors for survival. Of interest is the association of high levels of VEGF with good prognosis and higher levels of VEGF receptors with poor outcome. These data reflect the complexity by which angiogenic factors may affect the clinical behavior of patients with ALL, and this complexity should be considered in any therapeutic strategy incorporating antiangiogenic agents.

Angiogenesis Inducing Agents↗
PubMed2005

Adaptive randomized study of idarubicin and cytarabine alone or with interleukin-11 as induction therapy in patients aged 50 or above with acute myeloid leukemia or high-risk myelodysplastic syndromes.

A higher complete remission (CR) rate was observed in patients with acute myeloid leukemia (AML) who, on a prior randomized study of induction therapy, received gemtuzumab ozogamicin (GO) plus interleukin-11 (IL-11) rather than GO alone. An adaptive randomized phase III study of the addition of IL-11 to idarubicin and cytarabine (IA) induction in 100 patients >/=50 years of age with AML or high-risk myelodysplastic syndrome (MDS) was conducted. Median patient age was 67 years (range 50-82). Twenty-four of the 45 (53%) patients randomized to IA plus IL-11 achieved CR. Eight (33%) subsequently relapsed, 4 (17%) died in CR; median time to treatment failure (TTF) was 37 weeks. Twenty-nine of the 55 (53%) patients treated without IL-11 achieved CR. Eight (28%) subsequently relapsed, 2 (7%) died in CR; median TTF was 46 weeks. Median overall survivals were 21 and 59 weeks for the IA plus IL-11 and IA cohorts, respectively (p=0.271, log rank test; 0.435, Gehan-Breslow test). Ten episodes of the following grade 3 or 4 cardiopulmonary toxicities were observed in patients receiving IA plus IL-11, 12 such episodes in those receiving IA alone: atrial fibrillation, pleural effusions, myocardial infarction, bradycardia or hypotension. Two patients in each arm experienced grade 3 peripheral edema. There was no significant difference in incidence of any grade 3 or 4 adverse event, including thrombocytopenia, between treatment arms. There was no significant impact on CR rates, TTF, survival, or toxicity of adding an IL-11 regimen to IA induction in patients >/=50 years of age with AML.

Aged↗
PubMed2005

New approaches in the treatment of myelofibrosis.

Myelofibrosis with myeloid metaplasia (MMM) is a chronic clonal neoangiogenesis disorder characterized by bone marrow fibrosis and neoangiogensis with extramedullary hematopoiesis. Identification of prognostic factors associated with MMM have not impacted the treatment of the disease, which continues to be palliative with the exception of allogeneic stem cell transplantation (SCT) for potential long-term disease-free survival in selected patients. Additional insights into the pathophysiology of MMM have resulted in the use of novel therapeutic strategies in the treatment of this disease. The rationale for the investigation of these agents in MMM and the status of clinical trials with various modalities such as angiogenesis inhibitors (e.g., thalidomide), tyrosine kinase inhibitors (e.g., imatinib mesylate), farnesyl transferase inhibitors (e.g., R115777), and other agents are reviewed, in addition to the potential roles of autologous and allogeneic SCT.

Clinical Trials as Topic↗
PubMed2005

Clinical experience with decitabine in North American patients with myelodysplastic syndrome.

Recent evidence demonstrates that epigenetic silencing of genes is associated with myelodysplasia and that a worse prognosis may be correlated with hypermethylation of certain genes, such as the cyclin-dependent kinase inhibitor p15. 5-Aza-2'-deoxycytidine (decitabine, DAC) is a nucleoside analog, which, at low doses, acts as a hypomethylating agent and is fivefold to tenfold more active than 5-azacytidine (azacitidine, Vidaza)--currently the only approved drug for treatment of myelodysplastic syndrome (MDS). Clinical studies have demonstrated that decitabine has activity in patients with MDS. Preliminary results of a phase III multicenter North American trial comparing low-dose decitabine to supportive care verified that therapy with decitabine resulted in higher response rates, improved quality of life, and prolonged time to leukemic transformation and/or death. However, further elucidation of its mechanism of action is required, as clinical response to decitabine does not correlate with demethylation of the p15 gene promoter or the repetitive DNA element LINE. Decitabine appears to upregulate both hypermethylated and nonmethylated genes. Ongoing studies aim to determine the optimal dose, schedule, and route of administration of decitabine, and to evaluate whether efficacy can be improved by using it in combination with other agents, such as histone deacetylase inhibitors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Management of intracranial fungal infections in patients with haematological malignancies.

The incidence of, and mortality associated with, invasive fungal infections remains far higher than hoped. As a consequence of the overall increase in the incidence of such infections over time, the incidence of central nervous system (CNS) fungal infections is also increasing and, despite improvements in diagnostic techniques and the introduction of novel antifungal agents, therapy for CNS infections is still associated with discouragingly poor results. In patients with haematological malignancies, opportunistic infections with Candida or Aspergillus remain the most common infections affecting the CNS; however, opportunistic infections with less well-known fungi are becoming more common and must be considered in the differential diagnosis. New techniques for the early diagnosis of invasive fungal infections are emerging. Pharmacologic options for treating invasive fungal infections have also improved during the past few years, with new drugs becoming available that have broader antifungal spectra and better safety profiles. Other novel treatment approaches, such as combination therapy, are also being explored. Early investigations have produced encouraging results; however, large, prospective studies involving many patients are necessary to validate the widespread use of these approaches. This review analyses the existing guidelines for treatment of CNS fungal infections and the literature available on the use of new drugs to generate sets of recommendations for treatment of these life-threatening infections in patients with haematological malignancies.

Antifungal Agents↗
PubMed2005

Mammalian target of rapamycin as a therapeutic target in leukemia.

Reflecting its critical role in integrating cell growth and division with the cellular nutritional environment, the mammalian target of rapamycin *(mTOR) is a highly conserved downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway. mTOR activates both the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4E-binding protein-1. As a consequence of inhibiting its downstream messengers, mTOR inhibitors prevent cyclin-dependent kinase (CDK) activation, inhibit retinoblastoma protein phosphorylation, and accelerate the turnover of cyclin D1, leading to a deficiency of active CDK4/cyclin D1 complexes, all of which may help cause GI phase arrest. Constitutive activation of the PI3K/Akt kinases occur in human leukemias. FLT3, VEGF, and BCR-ABL mediate their activities via mTOR. New rapamycin analogs including CCI-779, RAD001, and AP23573, are entering clinical studies for patients with hematologic malignancies.

Everolimus↗
PubMed2005

Monoclonal antibodies in the treatment of leukemia.

MoAb-based therapies are evolving into the first broad-spectrum class of targeted anti-leukemic therapy. Developments in many areas, including computer modeling of receptors and ligands, and increasing sophistication in recombinant technologies may result in a rapid increase in the number and complexity of MoAb's available. We can anticipate an increase in the number of safer conjugates being delivered to leukemia cells. Further understanding of the in vitro mechanisms involved in tumor cell killing by MoAb will be important in maximizing the efficacy of this approach.

Alemtuzumab↗
PubMed2005

Targeting the kinase activity of the BCR-ABL fusion protein in patients with chronic myeloid leukemia.

Imatinib mesylate is a major advance in the therapy of patients with chronic myelogenous leukemia (CML). Imatinib mesylate binds to the inactive conformation of BCR-ABL tyrosine kinase suppressing the Philadelphia chromosome positive clone in CML. Clinical studies have yielded impressive results in all phases of CML. With higher rates of complete cytogenetic response with imatinib, molecular monitoring of disease is now advisable in assessing response and determining prognosis. Emergence of resistance to imatinib may be manifest at the hematologic, cytogenetic, or molecular levels in patients who remain in chronic phase, or may be evidenced by the development of more advanced CML phases. Resistance and eventual clinical failure of imatinib occurs in most patients with blastic phase disease. Resistance may occur at the level of Bcr-Abl, with reduction or loss of imatinib effectiveness as a kinase inhibitor, or, despite retention of its inhibitory ability, with changes in the ability to deliver an effective dose at the cellular level, and/or, the leukemia becoming less dependent on Bcr-Abl. The various mechanisms underlying these differing, non-mutually exclusive, mechanisms of resistance must be understood to develop corresponding therapeutic remedies. We review the current data on imatinib in CML, the criteria for diagnosis of imatinib resistance, and the mechanisms that underlie such resistance in CML.

Benzamides↗